Air pollution particulate matter <2.5 μm (PM_2.5) exposure is associated with poor respiratory outcomes. Mechanisms underlying PM_2.5-induced lung pathobiology are poorly understood but likely involve cellular and molecular changes to the airway epithelium. We extracted and chemically characterized the organic and water-soluble components of air pollution PM_2.5 samples, then determined the whole transcriptome response of human nasal mucociliary airway epithelial cultures to a dose series of PM_2.5 extracts. We found that PM_2.5 organic extract (OE), but not water-soluble extract, elicited a potent, dose-dependent transcriptomic response from the mucociliary epithelium. Exposure to a moderate OE dose modified the expression of 424 genes, including activation of aryl hydrocarbon receptor signaling and an IL-1 inflammatory program. We generated an OE-response gene network defined by eight functional enrichment groups, which exhibited high connectivity through CYP1A1, IL1A, and IL1B. This OE exposure also robustly activated a mucus secretory expression program (>100 genes), which included transcriptional drivers of mucus metaplasia (SPDEF and FOXA3). Exposure to a higher OE dose modified the expression of 1,240 genes and further exacerbated expression responses observed at the moderate dose, including the mucus secretory program. Moreover, the higher OE dose significantly increased the MUC5AC/MUC5B gel-forming mucin expression ratio and strongly downregulated ciliated cell expression programs, including key ciliating cell transcription factors (e.g., FOXJ1 and MCIDAS). Chronic OE stimulation induced mucus metaplasia–like remodeling characterized by increases in MUC5AC⁺ secretory cells and MUC5AC mucus secretions. This epithelial remodeling may underlie poor respiratory outcomes associated with high PM_2.5 exposure.

空气污染颗粒物 <2.5 μm (PM _2.5 ) 暴露与不良的呼吸结果相关。PM _2.5引起的肺部病理学的潜在机制知之甚少，但可能涉及气道上皮的细胞和分子变化。我们提取并化学表征了空气污染 PM _2.5样品的有机和水溶性成分，然后确定了人类鼻黏膜纤毛气道上皮培养物对 PM _2.5提取物剂量系列的整个转录组反应。我们发现 PM _2.5有机提取物（OE），而不是水溶性提取物，从粘液纤毛上皮引发了有效的、剂量依赖性的转录组学反应。暴露于中等剂量的 OE 会改变 424 种基因的表达，包括芳烃受体信号传导和 IL-1 炎症程序的激活。我们生成了一个由 8 个功能富集组定义的 OE 反应基因网络，它们通过CYP1A1、IL1A和IL1B表现出高连通性。这种 OE 暴露还强烈激活了粘液分泌表达程序（>100 个基因），其中包括粘液化生的转录驱动因子（SPDEF和FOXA3）。暴露于更高的 OE 剂量改变了 1,240 个基因的表达，并进一步加剧了在中等剂量下观察到的表达反应，包括粘液分泌程序。此外，较高的 OE 剂量显着增加了MUC5AC / MUC5B凝胶形成粘蛋白的表达比率，并强烈下调纤毛细胞表达程序，包括关键纤毛细胞转录因子（例如，FOXJ1和MCIDAS）。慢性 OE 刺激诱导粘液化生样重塑，其特征是 MUC5AC ⁺分泌细胞和 MUC5AC 粘液分泌物增加。这种上皮重塑可能是与高 PM _2.5暴露相关的不良呼吸结果的基础。